Integrating craniofacial morphology, oral function, temporomandibular biomechanics and mechanobiology to determine sex-specific TMJ pathophysiology in humans

项目摘要 颞下颌关节紊乱病影响约35万人在美国，3 - 8倍以上的妇女受到影响， 男人大约30%的颞下颌关节紊乱病患者经历颞下颌关节的机械功能障碍。 颞下颌关节（TMJ）中的关节盘（无血管组织），是口腔功能期间的承重关节。 然而，颞下颌关节盘功能障碍/移位（TMDD）亚群的病因学尚不清楚， 了解，包括为什么妇女受到不成比例的影响。合理的TMDD候选生物指示剂 包括颅面形态学、TMJ生物力学、椎间盘营养可用性和椎间盘代谢， 它们表现出不同程度的两性异形。这些因素相互作用，使得受试者特定的颅面 形态驱动TMJ生物力学，生物力学调节TMJ盘营养物质的利用和细胞 代谢/稳态。之前R01的研究结果证明，在猪中，无血管TMJ盘 营养环境在很大程度上取决于机械应变依赖的营养扩散， 环境对椎间盘细胞增殖和分化具有深远的影响，导致组织功能障碍。 因此，颞下颌关节生物力学和机械生物学的性别差异驱动的颅面 在人类中的形态学可能是关键的。我们的初步数据表明，人类颞下颌关节的性别差异 由于颅面形态的性别二态性，加上我们已经确定了颞下颌关节形态 表型也可以解释TMDD发生的性别差异。因此，现在有必要 确定机械应变依赖的养分运输特性和养分水平的性别差异- 人类颞下颌关节盘的依赖性能量代谢，并调查颅面的合理关联 形态学和TMJ生物力学通过机械生物学途径对TMDD的发展， 进展这项研究的中心假设是， 性别，以及健康对照组和TMDD患者之间，导致TMJ生物力学的差异， 椎间盘机械生物学可用于预测TMDD发展风险最大的个体， 进展长期目标是了解颞下颌关节紊乱病的机械生物学病因 疾病，以确定TMDD发展的特定风险因素，并定义TMDD机械生物学 进步的机制。通过识别潜在的形态学、生物力学和生物学 TMDD发展和进展的风险因素，这项工作具有很好的临床转化，并奠定了 未来人类研究的基础。拟议研究的具体成果包括： 颞下颌关节盘营养环境的机械应变依赖性及其对细胞活力的影响 以及人体组织中的能量代谢，增强了对受试者特异性形态学 导致颞下颌关节生物力学的受试者特异性差异，并识别TMDD特异性 机械生物学生物指示剂。

Project Summary Temporomandibular disorders affect ~35 million people in the US, with 3-8 times more women affected than men. Approximately 30% of temporomandibular disorder patients experience mechanical dysfunction of the articular disc (an avascular tissue) in the temporomandibular joint (TMJ), a load-bearing joint during oral function. However, the etiology of the temporomandibular disc dysfunction/displacement (TMDD) sub-population is poorly understood, including why women are disproportionately affected. Logical TMDD candidate bio-indicators include craniofacial morphology, TMJ biomechanics, disc nutrient availability, and disc metabolism, each of which show varying degrees of sexual dimorphism. These factors interact such that subject-specific craniofacial morphology drives TMJ biomechanics, and biomechanics regulates TMJ disc nutrient availability and cellular metabolism/homeostasis. Study results from the preceding R01 proved that in pigs the avascular TMJ disc nutrient environment is heavily dependent upon mechanical strain-dependent nutrient diffusion, and the nutrient environment has a profound effect on disc cell proliferation and differentiation leading to tissue dysfunction. Therefore, TMJ biomechanical and mechanobiological differences between sexes driven by craniofacial morphology in humans may be critical. Our preliminary data have demonstrated sex-differences in human TMJ loading due to sexual dimorphisms in craniofacial morphology, plus we have identified a TMJ morphologic phenotype that may also explain sex-differences in TMDD occurrence. Therefore, it is now necessary to determine sex differences in the mechanical strain-dependent nutrient transport properties and nutrient level- dependent energy metabolism of the human TMJ disc and investigate the plausible associations of craniofacial morphology and TMJ biomechanics through the mechanobiological pathway on TMDD development and progression. The central hypothesis of the proposed study is that craniofacial morphologic differences between sexes, as well as between healthy controls and TMDD patients, drive the differences of TMJ biomechanics and disc mechanobiology which can be used to predict individuals at greatest risk for TMDD development and progression. The long-term objectives are to understand the mechanobiological etiology of temporomandibular disorders, to identify risk factors specific for TMDD development, and to define TMDD mechanobiological mechanisms of progression. Through the identification of potential morphologic, biomechanical, and biological risk factors for TMDD development and progression, this work has promising clinical translation and lays the foundation for future human studies. Specific outcomes of the proposed study include: determination of the mechanical strain dependency of the temporomandibular disc nutrient environment and its impact on cell viability and energy metabolism in human tissues, an enhanced understanding of how subject-specific morphology results in subject-specific differences in temporomandibular biomechanics, and identification of TMDD-specific mechanobiological bio-indicators.